6-35575854-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004117.4(FKBP5):c.1355A>G(p.Lys452Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKBP5 NM_004117.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

Genes affected

FKBP5 (HGNC:3721): (FKBP prolyl isomerase 5) The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature hetero-oligomeric progesterone receptor complexes along with the 90 kDa heat shock protein and P23 protein. This gene has been found to have multiple polyadenylation sites. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

LOC101929309 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.091385335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP5	NM_004117.4	c.1355A>G	p.Lys452Arg	missense_variant	11/11	ENST00000357266.9
LOC101929309	XR_242006.4	n.182-17176T>C		intron_variant, non_coding_transcript_variant
FKBP5	NM_001145775.3	c.1355A>G	p.Lys452Arg	missense_variant	12/12
FKBP5	NM_001145776.2	c.1355A>G	p.Lys452Arg	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9	c.1355A>G	p.Lys452Arg	missense_variant	11/11	1	NM_004117.4	P1
FKBP5	ENST00000536438.5	c.1355A>G	p.Lys452Arg	missense_variant	12/12	1		P1
FKBP5	ENST00000539068.5	c.1355A>G	p.Lys452Arg	missense_variant	11/11	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.1355A>G (p.K452R) alteration is located in exon 12 (coding exon 10) of the FKBP5 gene. This alteration results from a A to G substitution at nucleotide position 1355, causing the lysine (K) at amino acid position 452 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.62	T;.;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.074
MutPred		0.23		Loss of ubiquitination at K452 (P = 6e-04);Loss of ubiquitination at K452 (P = 6e-04);Loss of ubiquitination at K452 (P = 6e-04);
MVP		0.93
MPC		0.25
ClinPred		0.076	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-35543631;